Inflammatory bowel disease (IBD) which includes Crohn's disease (CD) and ulverative colitis (UC) is a chronic idiopathic inflammatory disorder affecting the gatrointestine tract. Disease progression of CD and UC includes repeated episodes of inflammation and ulceration of the intestine, leading to complications requiring hospitalization, surgery and escalation of therapy (Peyrin-Biroulet et al., Am. J. Gastroenterol, 105: 289-297 (2010); Langholz E., Dan. Med. Bull., 46: 400-415 (1999)). Current treatments such as anti-tumor necrosis factor-alpha (TNF-α) biologics (e.g., infliximab (IFX), etanercept, adalimumab (ADL) and certolizumab pegol), thiopurine drugs (e.g., azathioprine (AZA), 6-mercaptopurin (6-MP)), anti-inflammatory drugs (e.g., mesalazine), and steroids (e.g., corticosteroids) have been shown to reduce disease activity. In some clinical trials of CD, mucosal healing which is described as the absence of intestinal ulcers, was induced in patients on combination therapy of corticosteroids, IFX and ADL. Furthermore, MH was maintained in patients receiving IFX.
Other studies have shown that mucosal healing can be a hallmark of suppression of bowel inflammation and predict long-term disease remission (Froslie et al., Gastroenterology, 133: 412-422 (2007); Baert et al., Gastroenterology, (2010)). Long-term mucosal healing has been associated with a decreased risk of colectomy and colorectal cancer in UC patients, a decreased need for corticosteroid treatment in CD patients, and possibly a decreased need for hospitalization (Dave et al., Gastroenterology & Hepatology, 8(1): 29-38 (2012)).
The International Organization for the Study of Inflammatory Bowel Disease proposed defining mucosal healing in UC as the absence of friability, blood, erosions an dulcers in all visualized segments of gut mucosa (D'Haens et al., Gastroenterology, 132: 763-786 (2007)). MH in CD was proposed to be the absence of ulcers. The gold standard for measurement of Crohn's disease activity is the Crohn's Disease Endoscopic Index of Severity (CDEIS). This disease index score is established from several variables such as superficial and deep ulceration, ulcerated and nonulcerated stenosis, and surface area of ulcerated and disease segments. A simplified version of the index is the Simple Endoscopic Score for Crohn's Disease, which takes into account disease variables including ulcer size, ulcerated surface, affected surface and presence of narrowing. Both indices evaluate clinical symptoms of CD, yet fail to measure the underlying cause of disease (e.g., inflammation) or resolution of disease (e.g., mucosal healing). A measurement of mucosal healing can be performed to assess disease induction as well as disease progression and resolution.
The process of mucosal healing begins with bleeding (e.g., degradation of the endothelial layers of the blood vessels) and inflammation, then progresses to cell and tissue proliferation, and finally tissue remodeling. At the inflammation stage, inflammatory markers and anti-inflammatory markers, such as, but not limited to, IL-1, IL-2, IL-6, IL-14, IL-17, TGFβ, and TNFα are expressed. During remodeling, tissue repair and remodeling growth factors, such as, but not limited to, AREG, EREG, HB-EGF, HGF, NRG1-4, BTC, EGF, IGF, TGF-α, VEGFs, FGFs, and TWEAK are expressed. Repair of the intestinal epithelium requires multiple signal transduction pathways which are necessary for cell survival, proliferation, and migration. We have identified novel markers of mucosal healing that are predictive of the risk of disease relapse and disease remission. A measurement of mucosal healing can be used to periodically assess disease status in patients receiving a therapy regimen.
Mucosal healing is typically assessed by endoscopy. Although the invasive procedure is considered to be low-risk, its cost and patient discomfort and compliance remain obstacles to frequent, regular endoscopies to assess mucosal healing. There is an unmet need in the art for non-invasive methods of determining mucosal healing in a patient.
There is a need in the art for methods of therapeutic management of diseases such as autoimmune disorders using an individualized approach to optimize therapy and monitor efficacy. The methods need to include assessing disease course and clinical parameters such as phamacokinetics, disease activity indices, disease burden, and mucosal status. The present invention satisfies this need and provides related advantages as well.